EBV is a human gamma herpesvirus with a tropism for B lymphocytes (Kieff and Liebowitz, in Virology, eds. Fields, B. N., Knipe, D. M. et al., p. 1889-1919, Raven Press, Ltd.: New York, 1990). Greater than 95% of the adult population carry EBV as a lifelong asymptomatic infection. However EBV has strong growth transforming capacities (Klein, Cell, 77:791-3, 1994), transforming B cells and presumably other cell types in a spectrum of EBV-associated malignancies including Hodgkin's lymphoma, nasopharyngeal carcinoma, T cell lymphoma, gastric carcinoma, and uterine leiomyosarcoma.
Three specific EBV genes are critical for tumorigenesis and induce cell proliferation as well as resistance to apoptosis (Gregory, et al., Nature, 349:612-4, 1991). EBNA-1 links as a dimer the viral origin of replication and the host cell DNA and ensures episomal replication during B cell growth (Bochkarev, et al., Cell, 84:791-800; Shah, et al., J. Virol., 66:3355-62, 1992). The two latent membrane proteins (LMP) have different roles. The C-terminal part of LMP1 can act as a direct oncogene (Wang, et al., Cell, 43:831-40, 1985) by mimicking CD40-mediated B cell activation (Busch and Bishop, J. Immunol., 162:2555-2561, 1999). Thus, LMP1 engages signaling proteins for the tumor necrosis factor receptor family (Mosialos, et al., Cell, 80:389-99, 1995) and protects against apoptosis by induction of bcl-2 (Henderson, et al., Cell, 65:1107-15, 1991). LMP2 mimics B cell receptor signaling by constitutively engaging syk and lyn, protein tyrosine kinases (Caldwell, et al., Immunity, 9:405-11, 1998). These three proteins appear to be the exclusive EBV genes that are expressed in most EBV-induced tumors (Miller, et al., in Virology, eds. Fields, B. N., Knipe, D. M. et al., p. 1921-1958, Raven Press, Ltd.: New York, 1990). In Burkitt's lymphoma, only EBNA-1 is required for EBV persistence, since transformation is achieved by an additional mechanism involving c-myc uncoupling through chromosomal translocation (Klein, supra).
The reason why most carriers of EBV avoid transformation remains to be elucidated. Immunity to EBNA-1 a priori could provide resistance to transformed cells, but it has proven difficult to detect specific T cell responses to this essential protein for EBV persistence. In fact, EBNA-1 blocks its own processing for MHC class I presentation (Blake, et al., Immunity, 7:791-802, 1997). This has been attributed to a deficit in proteasomal processing, caused by the N-terminal GA repeat domain (Levitskaya, et al., Nature, 375:68508, 1995). A similar GA stretch prevents IκBα degradation by the proteasome (Sharipo, et al., Nat Med., 4:939-44, 1998). Other EBV latency gene products are the focus of a strong MHC class I restricted CTL response, especially EBNA3A, 3B, and 3C (Steven, et al., J. Exp. Med., 184:1801-13, 1996). However, the EBNA3 proteins are not expressed in most of the EBV-associated tumors mentioned above, and instead are expressed in cultured transformed lines (B-LCL) and lymphoproliferative syndromes in immunosuppressed patients. CD8+ CTL responses to tumor-associated LMP1 (Khanna, et al., Eur. J. Immunol., 28:451-8, 1998) and LMP2 (Lee, et al., Eur. J. Immunol., 26:1875-83, 1996) proteins have been detected, but only occasionally.
It is becoming apparent that the development and persistence of effective CD8+ CTLs are dependent on CD4+ T cell help (Kalams and Walker, J. Exp. Med., 188:2199-204, 1998). Recognition of EBV products by CD4+ T cells has not been investigated in the same detail as the CD8+ response (Rickinson and Moss, Ann. Rev. Immunol., 15:405-31, 1997). Dendritic cells (DCs) are potent antigen presenting cells for CD4+ and CD8+ T cell immunity (Banchereau and Steinman, Nature, 392:245-52, 1998).
Thus, the efforts to identify a protective antigen in Epstein Barr Virus have been inconclusive, and it is unknown whether a single or multiple antigens are necessary to provide complete protection from infection. Furthermore, EBNA-1 is not believed to elicit protective immunity to the virus.